Aromatic acet amidoxime-o-carbamates

ABSTRACT

Aromatic acetamidoxime-O-carbamates are novel antihypertensive or antiinflammatory agents in warm-blooded animals.

United States Patent [191 Henderson June 26, 1973 AROMATIC ACET AMIDOXIME-O-CARBAMATES Inventor: Rosetta M. Henderson, Wilmington,

Del.

Assignee: E. I. DU Pont de Nemonrs and Company, Wilmington, Del.

Filed: Apr. 20, 1971 Appl. No.: 135,806

Int. Cl. C07c 123/00 [58] Field of Search 260/465 E, 564 260/566 AC, 501.14

[561- References Cited OTHER PUBLICATIONS Buyle et al., Helv. Chem. Acta, 46, 1073-83 (1963) Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Att0rneyAnth0ny P. Mentis 5 7] ABSTRACT Aromatic acetamidoxime-O-carbamates are novel antihypertensive or antiinflammatory agents in warmblooded animals.

12 Claims, No Drawings AROMATIC ACET AMIDOXIME-O-CARBAMATES CROSS REFERENCE TO RELATED APPLICATIONS This application is related to my earlier filed patent application Ser. No. 884,737, filed Dec. 12, 1969, which is a continuation-in-part of my application Ser. No. 789,959, filed Jan. 8, 1969 both of which are now abandoned.

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to a novel class of amidoxime- O-carbamates useful as antihypertensive or antiinflammatory agents.

Prior Art Amidoxime-O-carbamate compounds have been known since the work of Tiemann and Kruger [Ber. 17, 1685 (1884)]. The authors erroneously reported the compounds shown in their article as being oximes of ureides. R. Bryle, F. Eloy and R. Lanaers [Helv. Chim. Acta, 46, 1073 (1963)] later demonstrated that Tiemann and Kurgers reaction actually leads to O- carbamates of amidoximes and reported on a series of such compounds which they prepared. These prior art compounds are not known as being antihypertensive or antiinflammatory agents and differ structurally from the class of amidoxime-O-carbamates constituting the present invention.

Bell et a1. [Experientia, 23, 298 (1967)] and Hoppe et al. [Fed. Proc., 26, 459 (1967)] have reported certain indoleacetamidoximes as having antihypertensive activity in rats and dogs. The amide-O-carbamates of the present invention also differ structurally from these prior art compounds, being simpler and less costly to prepare.

SUMMARY OF THE INVENTION The invention relates to a compound selected from the group (A) having the formula wherein R and R alike or different, are H or alkyl of up to three carbon atoms;

R and R alike or different, are H or alkyl of up to three carbon atoms with the proviso that the sum of their carbon atoms does not exceed three;

Q is

a. an aryl radical of up to 12 carbon atoms; such aryl radical substituted with Br, Cl, F, I, N

CN, or lower alkyl, alkoxy, alkanoyl or (dialkylamino)alky1; or

HgCHgNKIHQ); (ilHa Preferred compounds within the scope of the above definition are those wherein Q is phenyl, thienyl or phenyl substituted with methyl, methoxy, F, C1, or N0 R, R and R are H; R is methyl.

Another embodiment of the invention relates to a method for treating hypertension in warm-blooded animals which comprises administering to said animal an antihypertensive amount of a compound of the invention.

A further embodiment relates to pharmaceutical compositions containing a compound of the invention in combination with suitable pharmaceutical adjuvants and modifiers.

The compounds of the invention are readily prepared from intermediates made according to the general procedure of F. Tiemann, Ber. 17, 126 (1884) which may be represented by equation (1) below:

The acetamidoxime-O-carbamates of the invention, where R R H, are conveniently prepared by reaction of the amidoximes of equation (1) in salt form, such as the hydrochloride salt, with an alkali metal cyamate as shown by equation (2) below:

/NH2 QCHRC\ -HX MOON NOH /NHI QCHRC 0 l NO- -NH2 MX where X an anion, e.g., chloride, bromide,sulfate,

phosphate or nitrate and M is a monovalent alkali metal cation.

The reaction of equation (2) is conducted inaqueous solvent such as dioxane, chloroform, diethyl ether, carbon tetrachloride, or the like. The reaction is conducted at a temperature between room temperature, i.e., about 25C, and the solvent reflux temperature, for

solution at a temperature between about -50C. and 5 a period of time between about 15 minutes and five is generally complete in 15 minutes to three hours. hours or longer.

Longer reaction times can be used but are not generally The salts of the amidoxime-O-carbamates of the innecessary. vention can be prepared by treating a solution of the The acetamidoxime-O-carbamates of the invention, compound with the acid of the salt desired. The solvent wherein R or R is alkyl, are prepared by reacting can be selected to provide a system in which the salt acetamidoximes of equation (I) with an isocyanate acformed is insoluble and therefore easily separated from cording to equation (3) below: the solution. Alternatively, a solvent system in which the end product salt is soluble can be employed and the solvent can be removed by evaporation. Q RNCO In general, the salts of the amidoxime-O-carbamates NH? 0 of the invention hydrolyze readily and thus are less de- QcHR b=N0- 3N sirable for use in formulating pharmaceutical compositions of the invention than the amidoxime-O- (3) carbamates per se.

The reaction of equation (3) is readily effected by E C EMB MENT F THE lNVENTlON stirring the amidoxime of equation (1) in a suitable sol- The preparation of the compounds of this invention Vent such as filoxane, ten'ahydmfmai ethy'l acetaiei is illustrated but not limited by the following examples chloroform, dlethyl ether, benzene or the like, lime in which all parts are by weight unless otherwise stated. adding the isocyanate at a rate to maintain temperatures from 050C. The reaction is generally complete EXAMPLE 1 in about 5 hours; however, some reactions are vigorous o Toiylacetiamidoxime o (N methylcarbamate) enough to be completed in about 0.5 hour. The products are sufficiently stable under reaction conditions that longer reaction times, e.g., up to 24 hours, do no harm and, for convenience, reaction periods lasting Q overnight can be used. "CH3; RECHE- The acetamidoxime-O-carbamates of the invention NH wherein both R and R are alkyl, are prepared by reacting the acetamidoximes of equation (1) with a car- CHFC benzene bamoyl chloride according to equation (4) below: N OH CHaNCO NH: QCHR(I]=NOH R R NCOCI 2 /NH2 NH; 0 a CHPC f cHR-r J=No-dN NTOTCNHCH (4) To a chilled solution 10-l 5C) of 16.2 g (0.1 mole) In equation (4) any carbamoyl halide can be used in of o-tolylacetamidoxime in 100 ml of benzene was place of the carbamoyl chloride shown. For example, added dropwise 5.7 g (0.1 mole) of methyl isocyanate one can use the carbamoyl fluoride, bromide or iodide in 25 ml of benzene. The solution was stirred for l but for economy and convenience the carbamoyl chlohour, concentrated under vacuum and the resulting ride is generally preferred. Solid was filtered and recrystallized from ethyl acetate.

The use of a base is not essential but when used may This yielded 10-03 g P Of the Carbamate as be any convenient acid-accepting compound that will a White Solid i g at C- combine with the acid by-product of the reaction. One Anal. Calcd. for C l-l N O may use alkali metal and alkaline earth metal oxides, C, 59.70; H, 6.84; N, 19.00 hydroxides, carbonates and bicarbonates. Organic C, 59.54; H, 6.92; N, 18.84. bases such as pyridme, quinolme, trialkylamines, and EXAMPLES 2 9 the like, are similarly useful.

The reaction of equation (4) is effected by adding the Example 1 was essentially repeated using reactants in carbamoyl halide to the amidoxime in a suitable inert which Q, R, R, R and R are as indicated.

- TABLE I Melting Reaction Crystallized carbolm- -Ill21 1 NE? Em Q R R1 R1 R3 point medium irom- Calcd. Found Calcd. Found Calcd. Found 2 H H OH; H USS-156.2 Dinxaue" Benzene- 49.69 49.47 5. 01 5.25 17.39 17. 17

ethanol.

3 ll [1 (111'; ll 132.8-134 Benzene "01110110."..- 53.33 62.91 5.37 5.3!) 18.6b 18.86

TABLE I( ontinued Carbon Hydro e Melting Reaetiou Crystallized h n Nitrogen Ex Q R 1 R2 R point medium Cnlcd. Found Calcd. Found Calcd. Found 4 H CH3 H 175.5176.5 .-.do..l' .-i d i 47.62 41.71 4.80 4.85 22.20 22.61

OzN-

5 H H CH3 H 172172.8 d0 Cyclohexanen 53.02 54.08 6. 11 6.38 15.72 15.70

OCH:

6 H H CH3 H 99.5402 do Ethyl acetatm 61.26 61.59 7. 7. 58 17.86 18. 08

H:C i

7 ([1113 II 11 C11: 11 13684364 (l0... Benzene 62.63 62.51 7.60 7.03 16.86 16.03

II3C@CH3 8 CH3 H CH3 H 158. 6-1504 -.do Ethanol 51.27 51.25 6.26 6.37 16.31 16. 33

9 H H CaHv H 68.5-69.3 .d0 Benzene- 62.63 62.58 7.68 7.44 16.86 16.50

hexane.

* Compound as H01 salt.

EXAMPLE l0 o-Tolylacetamidoxime-O-( N,N-dimethylcarbamate) CHaO OCH;

The compounds of this invention can be administered in the? treatment of hypertension and of inflammatory disease, as for example rheumatoid arthritis, by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal. For example, administration can be parenterally, i.e., subcutaneously, intravenously, intramuscularly, or intraperitoneally. Alternatively or concurrently, administration can be by the oral route.

The dosage administered will be dependent upon the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Generally, a daily dosage of active ingredient compound will be from about 0.01 to 50 mg/kg of body weight. Ordinarily, from 0.05 to 40 and preferably 0.1 to 20 mg/kg per day in one or more applications per day is effective to obtain desired results. For the more potent compounds of the invention, e.g., pchlorophenylacetamidoxime-O-( N-methyl carbamate the daily dosage ranges from about 0.01 to 20 mg/kg, preferably 0.05 to mg/kg, and more preferably 0.1 to 5 mg/kg.

The antihypertensive activity of the amidoxime-0- carbamates of the invention is evidenced by tests conducted in hypertensive rats and by further tests which show a blood pressure lowering action in normotensive dogs.

In a test involving rats, made hypertensive by repeated injections of desoxycorticosterone acetate (DOCA) according to the method described by Stanton and White [Arch. Intern. Pharmacodyn, 154, 351 (1965)], an acetamidoxime-O-(N- methylcarbamate) is injected intraperitoneally (i.p.) or orally into each of nine test animals on a cumulative dose schedule using three doses separated by a threefold increment. The compound is prepared in an aqueous polyvinyl alcohol-acacia vehicle and administered at a volume to body weight ratio of 5.0 ml/kg.

The first dose level is administered immediately after a control blood pressure reading, with the second and third levels following 2-hour and 4-hour blood pressure determinations, respectively. Systolic blood pressure is determined by a modification of the microphonemanometer technique [Friedman, M. and Freed, S. C., Proc. Soc. Exp. Biol. and Med. 70, 670 (1949)].

It is determined as a result of the test that 8 mg/kg of the compound p-chlorophenylacetamidoxime-O-(N- methylcarbamate) produces a 30 mm mercury (mm Hg) reduction in blood pressure from the pre-dose control value intraperitoneal (Effective Dose 30). Other compounds of the invention tested in a similar manner methylcarbamate) the i.p. ED value is less than 10 mg/kg.

The antiinflammatory activity of the amidoximecarbamates of the invention is evidenced by the inhibition of carrageenin-induced edema in the hind paw of rats in tests done according to the method of Winter, Risley and Nuss {Proc. Soc. Exp. Biol. and Med. 111, 544 (1962)].

Amidoximecarbamates of the invention were administered to male Carworth Farms CFE rats weighing about 100 grams by intubation as a solution in a PVA- Acacia medium (polyvinyl alcohol 1 percent, acacia 5 percent and methylparaben 0.1 percent) at a volume of 1 ml per 100 grams of body weight. Uniform hydration was provided by an additional volume of water equal to 2 ml per 100 grams of body weight. Each compound was administered orally at 300 mg/kg to six rats.

One hour after drug treatment, 0.5 ml of 1 percent carrageenin solution was injected into the plantar region of the right-hind paw of each rat. The volume of the foot was measured immediately after injection and again three hours later. The difference between the two volumes was the volume of induced edema. Foot volume was measured by immersion in mercury to an ink mark on the lateral malleolus. The mercury column was connected via a hydraulic system to a strain gauge. The output of the transducer was led to a Sanborn Transducer Amplifier, which was calibrated in terms of mercury displacement.

It is determined as a result of the test that compounds of the invention showed significant antiinflammatory activity as evidenced by the reduction in the volume of carrageenin-induced edema. For example, 300 mg/kg of the compound p-chlorophenylacetamidoxime-O-(N- methylcarbamate) produced a percent reduction in induced edema, 300 mg/kg of the compound 2,4,6- trimethylphenylacetamidoxime-O-carbamate produced a 39 percent reduction in induced edema, and 300 mg/kg of the compound 4- fluorophenylacetamidoxime-O-( N-methylcarbamate) produced an 81 percent reduction in induced edema. The compounds of this invention can be employed in useful pharmaceutical compositions in such dosage forms as tablets, capsules, powder packets or liquid solutions, suspensions or elixirs for oral administration or liquid for parenteral use, and in certain cases, suspensions for parenteral use (except intravenous injections). In such compositions, the active ingredient will ordinarily be present in an amount of at least 0.5 percent by weight based on the total weight of the composition and not more than 90 percent by weight.

Besides the active ingredient compound of this invention, the antihypertensive or antiinflammatory composition will contain a solid or liquid nontoxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. In the capsules will be from about 5-90 percent by weight of a compound of the invention and -10 percent of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets and powders will generally constitute from about 1 percent to about 95 percent and preferably from 5-90 percent by weight of active ingredient. These dosage forms preferably contain from about to about 500 mg of active ingredient, with about 7 to about 250 mg most preferred.

The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oil, including those of petroleum, animal, vegetable, and oils of synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. In general, water saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectible solutions. Sterile injectible solutions such as saline will ordinarily contain from about 05-25 percent and preferably about l-l0 percent by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.7-10 percent and preferably about l-5 percent, by weight. The pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Remingtons Pharmaceutical Sciences" by E. W. Martin, a well known reference text in this field.

Representative test data on the preferred antihypertensive or antiinflammatory agents of this invention are summarized in Table II where the data for the I.P.ED column were obtained when the compounds were tested on rats by the method of Stanton and White previously mentioned. The data for the percent Edema Reduction was obtained when the compounds were tested as previously described.

These represent the full structural formulas rather than the segment Q.

The following are illustrative examples of pharmaceutical compositions containing a compound of the invention.

EXAMPLE l 1 Tablets are prepared using conventional procedures and equipment. Each tablet contains mg. of pchloro-phenylacetamidoxime O-( N-methyl carba mate), 187.7 mg. mannitol, U.S.P., 0.3 mg. silicon dioxide, N.F., 3.0 mg. Povidone, N. F., and 9.0 mg. magnesium stearate, U.S.P.

Appropriate quantities of other tablet excipients may be used along with, or in place of, those mentioned above. For example, calcium stearate or stearic acid may be used as a lubricant, or talc may be used as a glidant or other binders such as Methocel" or Ethocel may be used.

EXAMPLE 12 No. 1 hard gelatin capsules are filled so that each capsule contains 200 mg. of 2,4,6-

trimethylphenylacetamidoxime-O-carbamate, 8 mg. of magnesium stearate, U.S.P., 32 mg. of talc, U.S.P. and mg. of mannitol, N.F.

. EXAMPLE 13 A mixture of 50 mg. of 4- fluorophenylacetamidoxime-O-(N-methyl carbamate) is prepared by milling the compound in 103 mg. soybean oil with 4 mg. of soy lecithin and 12 mg. of a mixture consisting of 1 part hydrogenated soybean oil, 1 part yellow wax, N'.F. and four parts food grade vegetable shortening. The resulting suspension is used to prepare soft gelatin capsules by means of a positive displacement pump.

EXAMPLE 14 A parenteral composition suitable for administration by injection is prepared by dissolving 1 percent by weight of a-methyl-phenyl acetamidoxime-O-(N- methylcarbamate) hydrochloride in sodium chloride injection, U.S.P. The solution is sterilized byfiltration.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

l. A compound selected from the group A. having the formula wherein R and R alike or different, are H or alkyl of up to three carbon atoms; R and R alike or different, are H or alkyl of up to three carbon atoms with the proviso that the sum of their carbon atoms does not exceed 3; Q is a. an aryl radical of up to 12 carbon atoms; such aryl radical substituted with Br, C], F, l, N0 CN, or lower alkyl, alkoxy, alkanoyl or (dialkylamino)alkyl; B. salts thereof with pharmaceutically acceptable acids (A). 2. A compound of claim 1 wherein R, R and R are H, R is methyl, and Q is phenyl, or phenyl substituted with methyl, methoxy, F, Cl or N0 3. A compound of claim 2 wherein Q is phenyl; phenylacetamidoxime-O-(N-methylcarbamate).

4. A compound of claim 2 wherein Q is o-tolyl; otolylacetamidoxime-O-( N-methylcarbamate 5. A compound of claim 2 wherein Q is pfluorophenyl; p-fluorophenylacetamidoxime-O-(N- methylcarbamate).

p-ch1orophenylacetamidoxime-O-(N- 9. A compound of claim 2 wherein Q is 3,4-dimethylphenyl; 3,4-dimethylphenylacetamidoxime-O-(N- methylcarbamate).

10. A compound of claim 2 wherein Q is 2,4,6- trimethylphenyl; 2,4,6-trimethylphenylacetamidoxime- O-(N-methylcarbamate) 11. A compound of claim 1 wherein R and R are each methyl, R and R are each hydrogen, and Q is phenyl; a-phenylpropionamidoxime-O-(N- methylcarbamate).

12. A compound of claim 1 wherein R and R are each hydrogen, R and R are each methyl, and Q is otolyl; o-tolylacetamidoxime-O-(N,N-dimethylcarbamate). 

2. A compound of claim 1 wherein R, R1 and R3 are H, R2 is methyl, and Q is phenyl, or phenyl substituted with methyl, methoxy, F, Cl or NO2.
 3. A compound of claim 2 wherein Q is phenyl; phenylacetamidoxime-O-(N-methylcarbamate).
 4. A compound of claim 2 wherein Q is o-tolyl; o-tolylacetamidoxime-O-(N-methylcarbamate).
 5. A compound of claim 2 wherein Q is p-fluorophenyl; p-fluorophenylacetamidoxime-O-(N-methylcarbamate).
 6. A compound of claim 2 wherein Q is p-chlorophenyl; p-chlorophenylacetamidoxime-O-(N-methylcarbamate).
 7. A compound of claim 2 wherein Q is p-nitrophenyl; p-nitrophenylacetamidoxime-O-(N-methylcarbamate).
 8. A compound of claim 2 wherein Q is 3,4-dimethoxy-phenyl; 3,4-dimethoxyphenylacetamidoxime-O-(N-methylcarbamate).
 9. A compound of claim 2 wherein Q is 3,4-dimethyl-phenyl; 3,4-dimethylphenylacetamidoxime-O-(N-methylcarbamate).
 10. A compound of claim 2 wherein Q is 2,4,6-trimethylphenyl; 2, 4,6-trimethylphenylacetamidoxime-O-(N-methylcarbamate).
 11. A compound of claim 1 wherein R and R2 are each methyl, R1 and R3 are each hydrogen, and Q is phenyl; Alpha -phenylpropionamidoxime-O-(N-methylcarbamate).
 12. A compound of claim 1 wherein R and R3 are each hydrogen, R1 and R2 are each methyl, and Q is o-tolyl; o-tolylacetamidoxime-O-(N,N-dimethylcarbamate). 